Altered Responses to Endoplasmic Reticulum Stress in Pancreatic Cancer

Pancreatic ductal adenocarcinoma (PDAC) represents the fourth most common cause of cancer-associated death in the United States. Little progress has been made in understanding how proteotoxic stress affects rapidly proliferating pancreatic tumor cells. Endoplasmic reticulum (ER) stress occurs when protein homeostasis in the ER lumen is perturbed. ER stress activates the unfolded protein response (UPR) to reduce the protein load in the ER. Under conditions of moderate ER stress, the UPR promotes cell cycle arrest which allows time for successful protein load reduction and enables cell survival. However, under conditions of high levels of ER stress the UPR induces cellular apoptosis. In this dissertation, I investigated the role of endoplasmic reticulum (ER) stress and its effects on the cell cycle in pancreatic cancer cells. Activation of the unfolded protein response after ER stress induction was determined by comparing expression of key UPR mediators in non-tumorigenic pancreatic ductal cells to pancreatic cancer cells. Two arms of the UPR were assessed: eIF2α/ATF4/CHOP and IRE1α/XBP1s. Pancreatic cancer cells exhibited altered UPR activation characterized by a delay in both phosphorylation of eIF2α and induction of spliced XBP1. Further evaluation of the UPR-mediated effects on cell cycle progression revealed that pancreatic cancer cells showed a compromised ability to inhibit G1 to S phase progression after ER stress. This reduced ability to arrest proliferation was found to be due to an impaired ability to downregulate cyclin D1, a key gatekeeper of the G1/S checkpoint. Abrogation of cyclin D1 repression was mediated through a slow induction of phosphorylation of eIF2α, a critical mediator of translational attenuation in response to ER stress. In conclusion, pancreatic cancer cells demonstrate a globally compromised ability to regulate the unfolded protein response. This deficiency results in reduced cyclin D1 repression through an eIF2α-mediated mechanism. These findings indicate that pancreatic cancer cells have increased tolerance for elevated ER stress compared to normal cells, and this tolerance results in continued tumor cell proliferation under proteotoxic conditions.

Developing a Framework for Child Welfare Supervision

The roles of the child welfare supervisor in guiding practice and in retaining child welfare workers are well established in the literature. In this article, we discuss a framework for child welfare supervision that was developed and implemented in the state of Iowa with support from the Children’s Bureau through a five-year grant to improve recruitment and retention in public child welfare. The framework supports family centered practice through a parallel process of supervision reflecting these guiding principles: strength-based, competency-based, culturally competent, reflective, individualized to workers’ learning styles and stages of development, and aimed at enhancing worker skill, autonomy, teamwork, and commitment to the organization. We present key elements of the framework, an overview of implementation, and evaluation results regarding knowledge gain, use of skills, and rates of worker retention.

Highlighting the Importance of Researching Family Homelessness

This invited commentary responds to and builds upon Tobin and Murphy's article, “Addressing the Challenges of Child and Family Homelessness.” In affirming the ideas emerging from this article, Hallett and Tierney provide three points of extension: (1) more research needs to be conducted with doubled-up families; (2) the role of shame needs further exploration; and, (3) additional work needs to be done to increase access to postsecondary institutions.