Head and neck squamous cell carcinoma (HNSCC) affects nearly 40,000 new patients each year. Despiteadvances in therapy mortality rates from HNSCC remain high due to the development of metastases andtherapy resistance. Tumor hypoxia is an important factor that determines the response of head and necksquamous cell carcinomas to surgery, chemotherapy and radiation treatment and is associated with worseclinical outcome. Such adaptations to therapy are linked in part to the ability of hypoxic tumor cells to slowdowncell cycle progression or enter a growth arrest/quiescent mode. However whether the therapy resistance ismerely due to the lack of proliferation or whether these cells can tap into pathways that can coordinate the cell-cycle arrest program to the upregulation of survival programs needs to be elucidated. One such pathway that isinduced during tumor hypoxia and can activate growth arrest and survival in a concerted manner is theendoplasmic reticulum (ER) stress response. In studying a human HNSCC cell line (T-HEp3) that istumorigenic and metastatic in vivo, we found that activation of p38 signaling induces G0/G1 arrest and dormantphenotype in vivo. Further these dormant HEp3 (D-HEp3) cells also displayed a p38-dependent increases inthe ER stress markers BiP/grp78 and PERK signaling. While both BiP and PERK promoted resistance tochemotherapeutic drug-induced apoptosis, only PERK activation contributed to the in vivo growtharrest/quiescence program. While the cytoprotective functions of BiP and PERK are known to promote tumorcell survival in vivo during hypoxia, whether the concurrent induction of PERK mediated quiescence is part ofthis adaptive mechanism need to be elucidated. We propose that similar to D-HEp3 cells, tumor cellswithin the hypoxic milieu of a growing tumor induce BiP and PERK regulated survival and growtharrest programs to promote therapy-resistance. A growing body of evidence suggests that tumor initiatingcells (TICs) in addition to propagating tumor growth, can also resist standard therapy regimens. It is thereforevital to identify mechanisms that specifically enable them to survive stress insults (chemo and radiotherapy)that can otherwise debulk most of the cancer cells. We have identified a TIC subpopulation that can not onlydrive the in vivo tumor growth in T-HEp3 cells but could also adopt a dormant behavior in response to stress.We hypothesize that TICs residing in the hypoxic regions of tumors rely on BiP and PERK mediatedsurvival and quiescence programs to resist therapy and that unlike majority of the tumor cells, TICscan activate a faster ER stress recovery mechanism that enables them to reverse PERK inducedquiescence and resume growth. We propose to examine (i) the mechanisms of BiP mediated therapyresistance in hypoxic tumor cells and (ii) whether PERK initiated survival and quiescence programs drivetreatment resistance of hypoxic tumor cells. We will also determine if this quiescence program is differentiallyregulated between TICs vs non-TICs.
We will explore whether ER stress signaling promotes therapy resistance by concomitantly activating survival and quiescence programs. Therapy resistance of hypoxic tumor cells is one of the major factors for the poor survival rates among head and neck cancer patients. The targets of this study will enable us to tailor novel combinatorial treatments that would sensitize the otherwise therapy insensitive quiescent hypoxic tumor cells to traditional therapeutics.
|Bragado, Paloma; Estrada, Yeriel; Sosa, Maria Soledad et al. (2012) Analysis of marker-defined HNSCC subpopulations reveals a dynamic regulation of tumor initiating properties. PLoS One 7:e29974|