Cell Competition in Carcinogenesis

Abstract

The majority of human cancers evolve over time through the stepwise accumulation of somatic mutations followed by clonal selection akin to Darwinian evolution. However, the in-depth mechanisms that govern clonal dynamics and selection remain elusive, particularly during the earliest stages of tissue transformation. Cell competition (CC), often referred to as 'survival of the fittest' at the cellular level, results in the elimination of less fit cells by their more fit neighbors supporting optimal organism health and function. Alternatively, CC may allow an uncontrolled expansion of super-fit cancer cells to outcompete their less fit neighbors thereby fueling tumorigenesis. Recent research discussed herein highlights the various non-cell-autonomous principles, including interclonal competition and cancer microenvironment competition supporting the ability of a tumor to progress from the initial stages to tissue colonization. In addition, we extend current insights from CC-mediated clonal interactions and selection in normal tissues to better comprehend those factors that contribute to cancer development.

Figure 1

1A: hFwe-mediated tumor-host cell competition regulates tumor outgrowth along the tumor-stroma border. (left) H&E staining of human colon cancer tissue demarcates tumor and stroma. hFwe^Win-expressing tumor cells compete with hFwe^Lose-expressing stromal cells within the microenvironment for space. Following cell fitness sensing and comparison, hFwe^Win cells outcompete and eliminate hFwe^Lose-stromal cells via apoptosis, creating space within which tumor cells can take over, resulting in tumor outgrowth at the expense of normal tissue. 1B: c-Myc-mediated cell competition drives cancer growth. (left) H&E staining of human lung cancer tissue demarcates tumor and stroma. Myc-high tumor cells outcompete Myc-low stromal cells, which undergo apoptosis. (right) Staining of human lung cancer sample shows high c-Myc protein in tumor cells and high caspase-3 (Cas3) in stroma cells, indicative of Myc-mediated competition-induced apoptosis. 1C: YAP–mediated cell competition mediates tumor outgrowth in liver cancer. (left) H&E staining of human liver cancer tissue demarcates tumor and stroma. Differential YAP expression between tumor cells (YAP-high) and peritumoral normal hepatocytes (YAP-low) along the tumor-stroma border results in YAP-induced cell competition resulting in expansion of YAP-high tumor cells and apoptosis of YAP-low peritumoral hepatocytes (Created with BioRender.com).

Figure 2

2A. In vivo model of Epithelial Defense against cancer (EDAC). (above) H&E demarcates tumor and stroma of human liver cancer overlaid by an animated depiction of YAP-mediated cell competition between tumor and stromal cells. (below) Within liver tissue, YAP-high peritumoral hepatocytes outcompete YAP-low liver tumor cells, which undergo apoptosis. This results in proliferation of YAP-high hepatocytes and inhibition of tumor outgrowth. 2B. In vitro intestinal organoid model of EDAC. Within the crypt domain of intestinal organoids, RasV12-transformed cells (red cell) surrounded by neighboring W.T. cells are sensed by W.T. cells and undergo apical extrusion. This results in the elimination of M.T. cells and prevention of tumor development. 2C. Inflammation suppresses CC and EDAC. (left) A tissue micro-environment burdened with chronic inflammation inhibits homeostatic cell competition between W.T. and M.T. cells, resulting in suppression of EDAC and thereby retention of M.T. cells. This leads to field cancerization and potentially tumor growth. (right) Targeting inflammation by COX2 inhibition or anti-inflammatory drugs restores cell competition and activates EDAC; W.T. cells eliminate M.T. cells, and tumor growth is suppressed. 2D. Mutant clone dynamics within normal human skin and mouse epidermis. (left) DNA sequencing of aged normal human skin reveals a high degree of genetic mutations resulting in a patchwork of M.T. clones, most likely due to lifetime of UV-exposure. Most frequent mutations were found in FGFR3, NOTCH1–3, FAT1, TP53. Also detected was a subclone containing FGFR3+TP53 mutations (size of clones relative to each other not drawn to scale). (right) Mouse epidermis exposed to U.V. U.V. exposure is highly mutagenic and generates a patchwork of M.T. clones. Short-term U.V. exposure results in GOF p53-M.T. epidermal progenitors that outcompete p53-W.T. progenitors and rapidly expand. Long-term U.V. exposure results in the out competition of p53-M.T. clones by M.T. clones with presumed increased fitness and competitive strength (Created with BioRender.com).

Figure 3

3A. CCO-deficiency as a result of mitochondrial DNA mutation. This process begins with a CCO-M.T. stem cell arising at the base of a CCO-W.T. colon crypt. Neutral stem cell competition results in niche succession and clonal conversion to a CCO-deficient crypt. M.T. crypts divide by fission creating a M.T. patch that competes for space with the colon mucosa. 3B. Crypts are able to fuse. Two phenotypically distinct crypts collide and begin to fuse in a process the reverse of fission. This results in two independent clones competing for the stem cell niche. The winner (in this scenario) is random but results in the removal of the loser from the colon. 3C. Mutations in TP53 drive cell competition in early fallopian tube precursors of ovarian cancer. The majority of high-grade serous carcinomas arise in the distal fallopian tube. Histology: Normal tubal epithelium is composed of ciliated and secretory cells. Acquisition of TP53 mutations, through the repetitive release of inflammatory follicular fluid during ovulation, confirms an advantage to secretory cells. Their expansion leads to the formation of p53 signatures. These cells stain strongly for p53 by immunohistochemistry. Subsequent alterations in oncogenes and tumor suppressors, like MYC, PTEN, RB, YAP1, or NOTCH1, among others, cooperate with M.T. TP53 to drive the transformation of the p53 signatures into serous tubal intraepithelial carcinoma (STIC lesions). STIC lesions retain strong staining for p53. STIC cells outcompete neighboring W.T. cells and eventually invade through the basement membrane to establish an invasive high-grade serous carcinoma (Created with BioRender.com).