Physical Poster + E-Poster Presentation 34th Lorne Cancer Conference 2022

Defining the heterogeneity of cellular function during growth and therapy resistance in colorectal cancer (#142)

Sara Hlavca 1 2 , Wing Hei Chan 1 2 , Rebekah Engel 1 2 3 , Thierry Jarde 1 2 4 5 , Paul McMurrick 3 , Helen Abud 1 2 3 4
  1. Anatomy and Developmental Biology, Monash University, Clayton, VIC, Australia
  2. Stem Cells and Development Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
  3. Cabrini Monash University Department of Surgery, Cabrini Hospital, Malvern, VIC, Australia
  4. Monash BDI Organoid Program, Monash Biomedicine Discovery Institute, Clayton, VIC, Australia
  5. Centre for Cancer Research, Hudson Institute of Medical Research, Clayton, VIC, Australia

One model of colorectal cancer describes the presence of a small subpopulation of tumour cells referred to as cancer stem cells (CSCs) that possess tumour-initiating potential, chemoresistance and have a greater propensity to metastasise1. Evidence for this model shows that patients with high expression of CSC markers, primarily LGR5, are linked to a worse prognosis and decreased disease-free survival2. Conversely, several groups have demonstrated that the CSC population is sensitive to chemotherapy3,4,5. The effect of this however is transient as the CSC population is soon repopulated by another resistant stem cell population1,5. Identifying this resistant stem cell may prove to be essential in ensuring the complete eradication of the CSC population during chemotherapy and prevention of tumour relapse. Recently, a unique stem cell population termed the revival stem cell (RevSC) was identified in the normal mouse intestine which is quiescent during homeostasis but proliferates following injury to repopulate the damaged LGR5+ population6. Therefore, this study hypothesises that the RevSC contributes to cellular heterogeneity in human colorectal tumours and likewise supports the CSCs during chemotherapy, which in turn has an effect on tumour progression and drug resistance. To identify the functional roles of the RevSC and CSC populations in tumour growth and drug resistance we chose to use self-organising three-dimensional organoid cultures which are shown to recapitulate key features of primary CRC tumours. We found that high expression of the RevSC marker gene, clusterin (CLU), is associated with increased relapse and decreased survival in a cohort of human CRC patients. CLU is also significantly upregulated in mouse organoid models of CRC following chemotherapeutic treatment, while LGR5 is downregulated. This is likewise observed in human patient-derived organoid models, suggesting that the CSC population could be chemo-sensitive whereas the RevSC population is resistant. Understanding the roles of these two different stem cell populations during tumour progression and chemotherapy treatment may provide insight to support the development of new targeted therapies for CRC.

  1. de Sousa e Melo, F., et al., A distinct role for Lgr5(+) stem cells in primary and metastatic colon cancer. Nature, 2017. 543(7647): p. 676-680.
  2. Merlos-Suárez, A., et al., The intestinal stem cell signature identifies colorectal cancer stem cells and predicts disease relapse. Cell Stem Cell, 2011. 8(5): p. 511-524.
  3. Planutis, A.K., et al., SW480 colorectal cancer cells that naturally express Lgr5 are more sensitive to the most common chemotherapeutic agents than Lgr5-negative SW480 cells. Anticancer Drugs, 2015. 26(9): p. 942-7.
  4. Metcalfe, C., et al., Lgr5+ stem cells are indispensable for radiation-induced intestinal regeneration. Cell Stem Cell, 2014. 14(2): p. 149-59.
  5. Asfaha, S., et al., Krt19+/Lgr5− cells are radioresistant cancer-initiating stem cells in the colon and intestine. Cell Stem Cell, 2015. 16(6): p. 627-638.
  6. Ayyaz, A., et al., Single-cell transcriptomes of the regenerating intestine reveal a revival stem cell. Nature, 2019. 569(7754): p. 121-125.