The colon is often thought of as one organ, but the right and left parts of the colon have different molecular features in cancers. New research in mice from investigators at theJohns Hopkins Kimmel Cancer Centerdemonstrates that these regions also have distinct transcriptional programs, or cellular processes, that regulate the development of normal and cancerous cells.
The transcription factor CDX2 -; which plays an important role in the development and function of the digestive system -; is a key mediator of these differences in proximal (right) colon stem cells, according to the research, which waspublished online Feb. 15inNature Communications. CDX2 has distinct roles in regulating stem cell differentiation in the proximal and distal (left) colon regions, the study finds. This distinction in stem cell regulation could help explain various features of colon cancers housed in these two areas of the colon.
In cancers, the proximal and distal regions of the colon have a tendency to house different gene mutations, explains senior study authorHariharan Easwaran, Ph.D., an associate professor of oncology at theJohns Hopkins University School of Medicine. For example, mutations in the BRAF gene contribute to cancers mainly in the proximal region, while mutations in the KRAS gene more commonly contribute to cancers in the distal colon and rectal regions. There also are a lot of epigenetic differences -; modifications to DNA that regulate whether genes are turned on or off -; between the two regions. The BRAF-driven proximal colon cancers are associated with a very high frequency of DNA methylation, a chemical modification of DNA, in gene regulatory elements such as the CpG islands.
BRAF mutations are associated with a poor prognosis in colon cancers. However, drugs that target mutations in BRAF haven't performed as well in colon cancers compared to other types of cancer such as melanoma, Easwaran says. "Dissecting this biology is important to understanding the basis for key differences in the molecular genetics and clinical features of these cancers, and in general for understanding why cancers arising within highly similar tissues in the colon may exhibit distinct features," he says.During the study, investigators derived proximal and distal colon organoids from 2-month-old mice, and introduced the BRAF cancer-causing gene. Organoids are lab-grown clusters of cells that resemble specific organs, such as the colon, and can grow indefinitely. They mimic the stem cell and differentiation patterns of the original tissue source, in this case, colon. The investigators identified small differences in gene expression in the proximal and distal colon-derived organoids. However, loss of CDX2 produced distinct differences in regulation of genes controlling stem cell and differentiation.
The investigators observed that CDX2 specifically promotes changes to stem cells in the proximal colon that allow typical cell differentiation into various cell types of the colon. But loss of CDX2 function instead causes them to become more primitive and stem-cell like. Because BRAF-mutant colon cancers are associated with loss of CDX2 expression, the investigators suppressed CDX2 in cells containing the BRAF mutation to see what would happen. In proximal colon stem cells, silencing CDX2 allowed BRAF mutations to drive tumor initiation in the stem cells, whereas in the distal colon, silencing CDX2 did not yield much change. The work found that CDX2 serves important roles in regulating stem and differentiated cell states, specifically in epithelial cells lining the proximal colon.
What this means is when CDX2 function is lost, it immediately alters the state of cells to promote tumor initiation in the proximal colon, whereas in the distal colon, this doesn't happen."
Lijing Yang, M.D., lead author, oncologist at Zhongnan Hospital of Wuhan University, China
Yang was at Johns Hopkins at the time the study was conducted. "There is something very different in how stem cells are regulated in these two regions, and underscores the potential for epigenetic factors in modulating tumor initiation differently in the proximal and distal colon," Yang says.
The work has implications for new combinations of existing therapies for colon cancers, such as drugs designed to inhibit the BRAF and KRAS genes, Easwaran says."Colon cancers are very notorious in that they develop resistance to these inhibitors," he says. "There's a lot of interest in trying to figure out how else we can actually improve the efficiency of these drugs."
Next steps are to try to determine what central mechanisms are occurring in the distal colon that reduce incidence of BRAF-driven tumors, and creates a higher likelihood for KRAS-driven cancers. "Our study shows that the transcriptional states regulating stem cell and differentiation states are important for the cancer driver mutations to drive cancers," Easwaran says. "It also helps explain why tumors arising in different anatomical locations may rely on different cancer-driving mutations. Therefore, determining the mechanisms will help identify novel ways of targeting critical dependencies for these oncogenic mutations."
Study co-authors were Lijing Yang, Daniel Petkovich, Sara-Jayne Thursby, Shilpa Bisht, Yiqing Mao, Ray-Whay Chiu Yen, Tina Largent, Cynthia Zahnow, Malcolm Brock, Kathy Gabrielson and Stephen B. Baylin; and Lei Tu of Huazhong University of Science and Technology in Wuhan, China.
The work was supported by grants from the National Cancer Institute (grant numbers R01CA229240, R01CA230995, and P30CA006973 [Kimmel Cancer Center Core Grant]); the National Institute of Environmental Health Sciences (number R01ES011858); and the Evelyn Grollman Glick Scholar Award.
Source:
Journal reference:
Yang, L., et al. (2024). Tissue-location-specific transcription programs drive tumor dependencies in colon cancer.Nature Communications. doi.org/10.1038/s41467-024-45605-4.
See the rest here:
Study reveals distinct molecular features of proximal and distal colon cancers - News-Medical.Net
- Congress Gives Stem Cells Another Shot -ASK THE EXPERT- ... [Last Updated On: August 4th, 2011] [Originally Added On: August 4th, 2011]
- Stem Cell Game 3- Grow with the Flow [Last Updated On: August 5th, 2011] [Originally Added On: August 5th, 2011]
- PROSTATE CANCER and stem cells [Last Updated On: August 13th, 2011] [Originally Added On: August 13th, 2011]
- Preview: 21st Century Snake Oil [Last Updated On: September 2nd, 2011] [Originally Added On: September 2nd, 2011]
- Stem cells: the future of medicine? [Last Updated On: September 5th, 2011] [Originally Added On: September 5th, 2011]
- Stem Cells: Politics vs. Medicine [Last Updated On: September 5th, 2011] [Originally Added On: September 5th, 2011]
- Mesenchymal Stem Cells in Regenerative Medicine: Of Hopes and Challenges [Last Updated On: September 5th, 2011] [Originally Added On: September 5th, 2011]
- An amazing story of stem cells, regenerative medicine and healing power: [Last Updated On: September 6th, 2011] [Originally Added On: September 6th, 2011]
- Preserving Stem Cells: Regenerative Medicine [Last Updated On: September 9th, 2011] [Originally Added On: September 9th, 2011]
- TEDxPhoenix - Jane Maienschein - Stem Cells, Regenerative Medicine and Us [Last Updated On: September 11th, 2011] [Originally Added On: September 11th, 2011]
- Personalized Medicine: Stem Cells 1/2 [Last Updated On: September 14th, 2011] [Originally Added On: September 14th, 2011]
- A Century of Stem Cells - Johns Hopkins Medicine [Last Updated On: September 16th, 2011] [Originally Added On: September 16th, 2011]
- What are stem cells? How can they be used for medical benefit? [Last Updated On: September 17th, 2011] [Originally Added On: September 17th, 2011]
- STEM CELLS TRANSLATIONAL MEDICINE Official Announcement [Last Updated On: September 18th, 2011] [Originally Added On: September 18th, 2011]
- Turning Adult Stem Cells into Medicine - Zannos Grekos, MD [Last Updated On: September 18th, 2011] [Originally Added On: September 18th, 2011]
- A New Era in Regenerative Medicine [Last Updated On: September 24th, 2011] [Originally Added On: September 24th, 2011]
- Bruce Conklin: Drug screening with stem cells [Last Updated On: September 27th, 2011] [Originally Added On: September 27th, 2011]
- Professors Chandran and ffrench-constant - Are stem cells the future of regenerative medicine? [Last Updated On: September 27th, 2011] [Originally Added On: September 27th, 2011]
- Hormone Myths vs. Medical Literature and How to Grow Your Own Stem Cells - Ronald Rothenberg, MD [Last Updated On: September 28th, 2011] [Originally Added On: September 28th, 2011]
- Cardiovascular Derivatives of Embryonic Stem Cells in Cardiac Repair and Drug Discovery [Last Updated On: September 29th, 2011] [Originally Added On: September 29th, 2011]
- Jackson Laboratory symposium: What's vital for effective stem cell therapies? [Last Updated On: September 30th, 2011] [Originally Added On: September 30th, 2011]
- Alzheimer's Disease: Spotlight on Stem Cell Research - Rod Shankle [Last Updated On: October 3rd, 2011] [Originally Added On: October 3rd, 2011]
- "StemEnhance" the Biggest Scientific [Last Updated On: October 4th, 2011] [Originally Added On: October 4th, 2011]
- Stem cell medical breakthrough? [Last Updated On: October 4th, 2011] [Originally Added On: October 4th, 2011]
- The Future of Stem Cells and Regenerative Medicine [Last Updated On: October 4th, 2011] [Originally Added On: October 4th, 2011]
- Stem Cell Clinical Trials : University of Miami Miller School of Medicine [Last Updated On: October 4th, 2011] [Originally Added On: October 4th, 2011]
- Medical tourism in Croatia - Regenerative medicine-Stem cells in reconstructive surgery [Last Updated On: October 4th, 2011] [Originally Added On: October 4th, 2011]
- Bioethics Stem Cells and the New Biology [Last Updated On: October 5th, 2011] [Originally Added On: October 5th, 2011]
- Stem Cells: The Hope The Hype and the Science [Last Updated On: October 5th, 2011] [Originally Added On: October 5th, 2011]
- Skin Stem Cells: Their Biology [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- Spotlight on Cancer Stem Cell Research [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- Lou Gehrig's Disease (ALS): UCSD Team's Stem Cell Therapy Rationale [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- Sickle Cell Anemia: Stem Cell Gene Therapy - Donald Kohn [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- Stem Cells and Parkinson's Disease [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- Stem Cell Research: Macular Degeneration [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- An amazing story of stem cells and regenerative medicine [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- Stem Cell City - Lisa Ray [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- Stem Cell Therapy: Healing Force of the future [Last Updated On: October 6th, 2011] [Originally Added On: October 6th, 2011]
- Adult Stem Cells in Drug Discovery and Therapeutics [Last Updated On: October 7th, 2011] [Originally Added On: October 7th, 2011]
- Medical Breakthrough: First Stem Cell Procedure [Last Updated On: October 7th, 2011] [Originally Added On: October 7th, 2011]
- Dr. Judith Oppenheim, Chicago on Dental Stem Cells on WGN-TV's Medical Watch. [Last Updated On: October 9th, 2011] [Originally Added On: October 9th, 2011]
- Jerome Zack: Creating iPS Cells - Video [Last Updated On: October 14th, 2011] [Originally Added On: October 14th, 2011]
- Sight for sore eyes - Video [Last Updated On: October 15th, 2011] [Originally Added On: October 15th, 2011]
- Regenerative Medicine Update: Stem Cells and Functional Testing - Mitchell J. Ghen, DO, PhD - Video [Last Updated On: October 15th, 2011] [Originally Added On: October 15th, 2011]
- Stem cells as the future of medicine - Video [Last Updated On: October 18th, 2011] [Originally Added On: October 18th, 2011]
- Neural Stem Cells Reverse Alzheimer's-Like Symptoms - Video [Last Updated On: October 19th, 2011] [Originally Added On: October 19th, 2011]
- Deafness: Spotlight on Stem Cell Research - Ebenezer Yamoah - Video [Last Updated On: October 21st, 2011] [Originally Added On: October 21st, 2011]
- Leukemia: Spotlight on Stem Cell Research - Patient Stories - Video [Last Updated On: October 21st, 2011] [Originally Added On: October 21st, 2011]
- Epidermolysis Bullosa: Corrected iPS Stem Cell-Based Therapy - Video [Last Updated On: October 21st, 2011] [Originally Added On: October 21st, 2011]
- iPS Stem Cell-Based Treatment of Epidermolysis Bullosa - Video [Last Updated On: October 21st, 2011] [Originally Added On: October 21st, 2011]
- Parkinson's Disease: Spotlight on Stem Cell Research - Arnold Kriegstein - Video [Last Updated On: October 21st, 2011] [Originally Added On: October 21st, 2011]
- Closing Remarks, Screening Stem Cells 2009: From Reprogramming to Regenerative Medicine - Video [Last Updated On: October 23rd, 2011] [Originally Added On: October 23rd, 2011]
- The Sue and Bill Gross Stem Cell Regenerative Medicine Center at UCI - Video [Last Updated On: October 26th, 2011] [Originally Added On: October 26th, 2011]
- Stem Cell Institute - Video [Last Updated On: October 28th, 2011] [Originally Added On: October 28th, 2011]
- StemCellTV Special Report - Stem Cell Therapy a "Medical Game Changer" - Video [Last Updated On: October 28th, 2011] [Originally Added On: October 28th, 2011]
- Adult Stem Cells and Regeneration - Video [Last Updated On: November 8th, 2011] [Originally Added On: November 8th, 2011]
- Cloned Embryonic Stem Cells, FIRST (Brainstorm Ep26) - Video [Last Updated On: November 12th, 2011] [Originally Added On: November 12th, 2011]
- Beating Heart Stem Cells - Video [Last Updated On: November 13th, 2011] [Originally Added On: November 13th, 2011]
- Stem Cell Research In Toronto - Video [Last Updated On: November 13th, 2011] [Originally Added On: November 13th, 2011]
- Stem Cells and Their Amazing Potential 2011 trailer - Video [Last Updated On: November 15th, 2011] [Originally Added On: November 15th, 2011]
- Stemcell Research and Aging - Panel 1 - Video [Last Updated On: December 13th, 2011] [Originally Added On: December 13th, 2011]
- Austin Forum - Nov 1st (Part 4 of 4) - Video [Last Updated On: December 13th, 2011] [Originally Added On: December 13th, 2011]
- Vet-Stem Medistem Cellmedicine Rheumatoid Arthritis Stem Cell Video - Video [Last Updated On: December 19th, 2011] [Originally Added On: December 19th, 2011]
- Stem Cell Clinical Trial for Heart Failure: Eduardo Marban - CIRM Spotlight on Disease - Video [Last Updated On: December 26th, 2011] [Originally Added On: December 26th, 2011]
- Stem Cell-Derived Heart Cells: Bruce Conklin - CIRM Science Writer's Seminar - Video [Last Updated On: January 5th, 2012] [Originally Added On: January 5th, 2012]
- Pope gives support to adult stem cells and asks for ethics in scientific research - Video [Last Updated On: January 5th, 2012] [Originally Added On: January 5th, 2012]
- Stem Cell Treatment for Rheumatoid Arthritis - Darnell Morris - Video [Last Updated On: January 5th, 2012] [Originally Added On: January 5th, 2012]
- Personalized Medicine: Stem Cells 2/2 - Video [Last Updated On: January 13th, 2012] [Originally Added On: January 13th, 2012]
- Utilizing Stem Cell-derived Cardiomyocytes for Early Safety Screening - Webinar Presentation - Video [Last Updated On: January 22nd, 2012] [Originally Added On: January 22nd, 2012]
- Stem Cell Stage Bypassed in Skin Cell to Brain Cell Transformation [Last Updated On: February 1st, 2012] [Originally Added On: February 1st, 2012]
- Encouraging Results with Stem Cell Transplant for Brain Injury [Last Updated On: February 1st, 2012] [Originally Added On: February 1st, 2012]
- Stem cell injection successfully treats urinary incontinence [Last Updated On: February 13th, 2012] [Originally Added On: February 13th, 2012]
- ImmunoCellular Therapeutics To Present at Targeting Stem Cells Symposium during 19th Annual Molecular Medicine Tri ... [Last Updated On: February 17th, 2012] [Originally Added On: February 17th, 2012]
- Adult Stem Cell Success Stories - Barry Goudy - Video [Last Updated On: February 21st, 2012] [Originally Added On: February 21st, 2012]
- Stem Cell Treatment for T-6 Spinal Cord Injury - Video [Last Updated On: February 21st, 2012] [Originally Added On: February 21st, 2012]
- Stem Cells China-Switzerland.wmv - Video [Last Updated On: February 21st, 2012] [Originally Added On: February 21st, 2012]
- Stem cell find offers hope for infertility [Last Updated On: February 27th, 2012] [Originally Added On: February 27th, 2012]
- Stem cell fertility treatments could be risky for older women [Last Updated On: February 28th, 2012] [Originally Added On: February 28th, 2012]
- A*STAR Scientists Make Groundbreaking Discovery on Stem Cell Regulation [Last Updated On: March 1st, 2012] [Originally Added On: March 1st, 2012]
- UGA study reveals basic molecular 'wiring' of stem cells [Last Updated On: March 1st, 2012] [Originally Added On: March 1st, 2012]