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Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive disease with limited and, very often, ineffective medical and surgical therapeutic options. The treatment of patients with advanced unresectable PDAC is restricted to systemic chemotherapy, a therapeutic intervention to which most eventually develop resistance. Recently, nab-paclitaxel (n-PTX) has been added to the arsenal of first-line therapies, and the combination of gemcitabine and n-PTX has modestly prolonged median overall survival. However, patients almost invariably succumb to the disease, and little is known about the mechanisms underlying n-PTX resistance. Using the conditionally reprogrammed (CR) cell approach, we established and verified continuously growing cell cultures from treatment-naïve patients with PDAC. To study the mechanisms of primary drug resistance, nab-paclitaxel-resistant (n-PTX-R) cells were generated from primary cultures and drug resistance was verified in vivo, both in zebrafish and in athymic nude mouse xenograft models. Molecular analyses identified the sustained induction of c-MYC in the n-PTX-R cells. Depletion of c-MYC restored n-PTX sensitivity, as did treatment with either the MEK inhibitor, trametinib, or a small-molecule activator of protein phosphatase 2a. IMPLICATIONS: The strategies we have devised, including the patient-derived primary cells and the unique, drug-resistant isogenic cells, are rapid and easily applied in vitro and in vivo platforms to better understand the mechanisms of drug resistance and for defining effective therapeutic options on a patient by patient basis.

NOAA Daily Optimum Interpolation Sea Surface Temperature (DOISST) and other similar sea surface temperature (SST) products indicate that the globally averaged SST set a new daily record in March 2023. The record‐high SST in March was immediately broken in April, and new daily records were set again in July and August 2023. The SST anomaly (SSTA) persisted at a record high from mid‐March to the remainder of 2023. Our analysis indicates that the record‐high SSTs, and associated marine heatwaves (MHWs) and even super‐MHWs, are attributed to three factors: (a) a long‐term warming trend, (b) a shift to the warm phase of the multi‐decadal Pacific‐Atlantic‐Arctic (PAA) mode, and (c) the transition from the triple‐dip succession of La Niña events to the 2023–24 El Niño event. Plain Language Summary: Observation‐based analyses such as the NOAA DOISST show that global mean SST reached a record high in April 2023, breaking the previous record of global mean SST set in March 2016, and the April 2023 record of global mean SST was broken again in July and August 2023. Our study indicates that these record‐breaking SSTs in 2023 resulted from record‐high SSTs over much of the global oceans and associated with widespread marine heatwaves (MHWs). Further analyses show that the record‐high SSTs are attributed to a long‐term‐warming trend associated with increasing greenhouse gases, a shift to the warm phase of a multidecadal Pacific‐Atlantic‐Arctic (PAA) mode, and a warming associated with the transition from 2020–23 La Niña events to the 2023–24 El Niño event. Key Points: Global mean sea surface temperature (SST) in 2023 set a record highRecord‐high SST was associated with widespread marine heatwaves (MHWs) and super‐MHWs throughout the oceansRecord‐high SST was attributed to the multi‐decadal warming trend, warm phase of Pacific‐Atlantic‐Arctic mode, and 2023–24 El Niño event [ABSTRACT FROM AUTHOR]

Merlin encoded by the Nf2 gene is a bona fide tumor suppressor that has been implicated in regulation of both the Hippo-Yap and Rac1-Pak1 pathways. Using genetically engineered murine liver models, we show that co-deletion of Rac1 with Nf2 blocks tumor initiation but paradoxically exacerbates hepatomegaly induced by Nf2 loss, which can be suppressed either by treatment with pro-oxidants or by co-deletion of Yap. Our results suggest that while Yap acts as the central driver of proliferation during Nf2 tumorigenesis, Rac1 primarily functions as an inflammation switch by inducing reactive oxygen species that, on one hand, induce nuclear factor κB signaling and expression of inflammatory cytokines, and on the other activate p53 checkpoint and senescence programs dampening the cyclin D1-pRb-E2F1 pathway. Interestingly, senescence markers are associated with benign NF2 tumors but not with malignant NF2 mutant mesotheliomas, suggesting that senescence may underlie the benign nature of most NF2 tumors.

CD133, a cancer stem cell (CSC) marker in tumors, including melanoma, is associated with tumor recurrence, chemoresistance, and metastasis. Patient-derived melanoma cell lines were transduced with a Tet-on vector expressing CD133, generating doxycycline (Dox)-inducible cell lines. Cells were exposed to Dox for 24 h to induce CD133 expression, followed by RNA-seq and bioinformatic analyses, revealing genes and pathways that are significantly up- or downregulated by CD133. The most significantly upregulated gene after CD133 was amphiregulin (AREG), validated by qRT-PCR and immunoblot analyses. Induced CD133 expression significantly increased cell growth, percentage of cells in S-phase, BrdU incorporation into nascent DNA, and PCNA levels, indicating that CD133 stimulates cell proliferation. CD133 induction also activated EGFR and the MAPK pathway. Potential mechanisms highlighting the role(s) of CD133 and AREG in melanoma CSC were further delineated using AREG/EGFR inhibitors or siRNA knockdown of AREG mRNA. Treatment with the EGFR inhibitor gefitinib blocked CD133-induced cell growth increase and MAPK pathway activation. Importantly, siRNA knockdown of AREG reversed the stimulatory effects of CD133 on cell growth, indicating that AREG mediates the effects of CD133 on cell proliferation, thus serving as an attractive target for novel combinatorial therapeutics in melanoma and cancers with overexpression of both CD133 and AREG. [ABSTRACT FROM AUTHOR]