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. 2020 Feb 20;12(2):85-98.
doi: 10.1093/jmcb/mjy080.

SOX2 in cancer stemness: tumor malignancy and therapeutic potentials

Mahfuz Al Mamun  1 , Kaiissar Mannoor  2 , Jun Cao  1 , Firdausi Qadri  2 , Xiaoyuan Song  1   3
Affiliations

SOX2 in cancer stemness: tumor malignancy and therapeutic potentials

Mahfuz Al Mamun et al. J Mol Cell Biol. .

Abstract

Cancer stem cells (CSCs), a minor subpopulation of tumor bulks with self-renewal and seeding capacity to generate new tumors, posit a significant challenge to develop effective and long-lasting anti-cancer therapies. The emergence of drug resistance appears upon failure of chemo-/radiation therapy to eradicate the CSCs, thereby leading to CSC-mediated clinical relapse. Accumulating evidence suggests that transcription factor SOX2, a master regulator of embryonic and induced pluripotent stem cells, drives cancer stemness, fuels tumor initiation, and contributes to tumor aggressiveness through major drug resistance mechanisms like epithelial-to-mesenchymal transition, ATP-binding cassette drug transporters, anti-apoptotic and/or pro-survival signaling, lineage plasticity, and evasion of immune surveillance. Gaining a better insight and comprehensive interrogation into the mechanistic basis of SOX2-mediated generation of CSCs and treatment failure might therefore lead to new therapeutic targets involving CSC-specific anti-cancer strategies.

Keywords: SOX2; cancer stem cells (CSCs); drug resistance; therapeutic potentials.

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Figures

Figure 1
Figure 1
SOX2 as a key driver in cancer stemness. (A and B) SOX2+ tumor cells are relatively quiescent, avoid chemotherapy, reinitiate tumor growth, and give rise to differentiated cell progenies that recapitulate primary tumor compositions. (A) Anti-tumor therapy kills most of the tumor cells, leaving behind SOX2+ tumor cells that serve as CSCs for tumor regrowth. Lineage tracing experiments showed that developmental hierarchies were preserved, and SOX2+ tumor cells were therapy resistant and responsible for tumor progression. (B) The representative image shows enrichment of (quiescent) SOX2+ tumor cells from tumor masses, which seed for new tumors containing both SOX2+ and SOX2− tumor cells (left). Lineage-specific ablation of SOX2+ tumor cells or conditional SOX2 deletion leads to tumor regression (right). (C) High SOX2 and PRKCI expressions in LSCC gain via 3q26 chromosomal amplification. Coordinated overexpression of both of these proteins is attributed to LSCC stemness and enhanced tumorigenicity. Since 3q26 copy number gains are the most frequently occurring mutation in SOC, cervical, head and neck, oral, and esophageal carcinomas, it might be involved in the generation of respective CSCs.
Figure 2
Figure 2
Mechanistic links to SOX2-dependent CSC-mediated clinical relapse. (A) SOX2 mediates survival signal to CSCs. In SOC CSCs, elevated SOX2 expression is associated with upregulation of anti-apoptotic factor BCL2 and suppression of pro-apoptotic proteins PUMA and NOXA. This provides survival signal to persist under anti-cancer drugs as carbolatin, cisplatin, or paclitaxel, and thus, enhancing apoptotic resistance. (B) CSCs gain partial EMT phenotypes facilitating tumor malignancy due to SOX2 expression. It illustrates the extent of invasiveness, tumor-initiating ability, and a change in degree of drug resistance across the spectrum of EMT-program activation. Tumor invasiveness and drug resistance increase upon gaining complete EMT phenotypes. The cancer stemness or tumor-initiating ability of carcinoma cells is influenced by the level of EMT-program activation and it peaks at an intermediate level of EMT. Indeed, extensive EMT activation is usually detrimental to tumor-initiating ability. The drug resistance of carcinoma cells also seems to be maximal at an intermediate level of EMT-program activation, but plateaus (rather than declines) with further activation of this program. In pancreatic adenocarcinoma (PADC), SOX2 expression imparts partial EMT-like phenotypes to PADC CSCs via upregulation of the EMT master regulators SNAIL, SLUG, and TWIST, and it is shown that SOX2 cannot induce fully EMT program in PADC. Thus, SOX2 contributes to EMT-mediated tumor malignancy. MET, mesenchymal-to-epithelial transition. (C) SOX2 mediates drug efflux in CSCs. SOX2 in CSCs enhances the expression of ABC drug transporters that can effectively efflux anti-cancers drugs (e.g. cisplatin, and paclitaxel) from glioblastoma (GBM), breast cancer, gastric cancer, and HNSCC CSCs through hydrolysis of ATP. Thus, CSCs acquire resistance to therapy and cause clinical failure. CSCs are likely to share many properties of normal stem cells providing an opportunity for a long lifespan, e.g. they remain relative quiescence, show resistance to drugs, and efflux toxins through expression of ABC transporters. This points to the tumors having built-in population of drug-resistant pluripotent cells that can survive chemotherapy and repopulate the tumor. (D) SOX2 mediates evasion of complement surveillance by CSCs. High SOX2 expression in epithelial CSCs causes upregulation of CD59, which in turn leads to inhibition of membrane attack complex (MAC). Thus, CSCs avoid complement attacks and show enhanced resistance to CDC. (E) SOX2 promotes lineage plasticity in p53−/− and Rb−/− prostate cancers. SOX2 is responsible for anti-androgen resistance in castration-resistant prostate cancers of adenocarcinoma histology (CRPC-adeno) due to TP53 and RB1 alterations (TP53Alt, RB1Alt) compared to those with WT TP53 and RB1 (TP53WT, RB1WT). High SOX2 expression leads to anti-androgen drug resistance (e.g. enzalutamide) in CRPC-adeno upon loss of tumor suppressor genes p53 and Rb. Luminal identity is characterized by the presence of androgen receptor (AR). The tumors can develop resistance to the anti-androgen drug by a phenotypic shift from androgen receptor (AR)-dependent luminal epithelial cells to AR-independent basal-like cells with mixed phenotypes (luminal/basal/neuroendocrine cells). (F) SOX2 provides lineage plasticity to CSCs. In skin SCC, SOX2+ tumor-propagating cells give rise to both SOX2-expressing and SOX2-negative tumor cell progenies, thus, imparting plasticity to CSCs. (G) SOX2 involves in lineage-specific survival mechanism. SOX2 overexpression gives rise to LSCC upon loss of the tumor suppressor Lkb or LADC upon loss of p53 and/or Rb.
Figure 3
Figure 3
SOX2-expressing tumor cells as potential therapeutic targets. (A) Anti-mitotic chemotherapy (e.g. cytarabine) and sonic hedgehog (SHH) pathway inhibitor (e.g. vismodegib) fail to kill SOX2+ MPCs and cause CSC-mediated clinical relapse (left). Mithramycin, a highly effective drug against SOX2+ mouse and human SHH medulloblastoma cells, can target SOX2+ MPCs in vitro and stop tumor regrowth (right). (B) In LSCC, SOX2 is overexpressed due to copy number gain at 3q26.33. LSD1 is highly expressed in SOX2+ LSCC cells. Inhibition of LSD1 expression by LSD1 inhibitors effectively reduces SOX2 expression, thereby suppressing generation of CSCs and oncogenic potentiality of SOX2-dependent lineage-specific survival in SOX2+ tumors. (C) Potentiality of vaccine development targeting SOX2 in NSCLC patients. About 50% NSCLC patients could elicit SOX2-specific CD8+ T cell immune responses while the remaining 50% patients could not. SOX2-specific immune responses are amplified upon administration of anti-PD-1 immunotherapy to patients with SOX2-specific CD8+ T cells, thus, leading to the tumor regression. The rest of the patients lacking SOX2-specific T lymphocytes fail to respond to anti-PD-1 immunotherapy, resulting in disease relapse, and thus can constitute ideal candidates for SOX2-targeting vaccines. APC, antigen presenting cell; MHC, major histopatibility complex; TCR, T cell receptor.
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