Crucial transitions in cancer-including tumor initiation, local expansion, metastasis, and therapeutic resistance-involve complex interactions between cells within the dynamic tumor ecosystem. Transformative single-cell genomics technologies and spatial multiplex in situ methods now provide an opportunity to interrogate this complexity at unprecedented resolution. The Human Tumor Atlas Network (HTAN), part of the National Cancer Institute (NCI) Cancer Moonshot Initiative, will establish a clinical, experimental, computational, and organizational framework to generate informative and accessible three-dimensional atlases of cancer transitions for a diverse set of tumor types. This effort complements both ongoing efforts to map healthy organs and previous largescale cancer genomics approaches focused on bulk sequencing at a single point in time. Generating single-cell, multiparametric, longitudinal atlases and integrating them with clinical outcomes should help identify novel predictive biomarkers and features as well as therapeutically relevant cell types, cell states, and cellular interactions across transitions. The resulting tumor atlases should have a profound impact on our understanding of cancer biology and have the potential to improve cancer detection, prevention, and therapeutic discovery for better precision-medicine treatments of cancer patients and those at risk for cancer.Cancer forms and progresses through a series of critical transitions-from pre-malignant to malignant states, from locally contained to metastatic disease, and from treatment-responsive to treatment-resistant tumors (Figure 1). Although specifics differ across tumor types and patients, all transitions involve complex dynamic interactions between diverse pre-malignant, malignant, and non-malignant cells (e.g., stroma cells and immune cells), often organized in specific patterns within the tumor

Background Several grading schemes for the extent of residual tumor in post-treatment pancreaticoduodenectomy (PD) specimens have been proposed. However, the prognostic significance of these grading schemes is unknown. Methods Histopathologic slides of 223 cases who received neoadjuvant chemoradiation and PD were reviewed. The extent of residual tumor was graded using both the College of American Pathologists (CAP) and the Evans grading systems. The grading results were correlated with clinicopathological parameters and survival. Results Among the 223 patients, 6 patients (2.7%) showed pathologic complete response (pCR, CAP Grade 0 or Evans grade IV), 36 cases (16.1%) with minimal residual tumor (CAP Grade 1 or Evans grade III), 124 cases (55.6%) with moderate response (CAP Grade 2 or Evans grade IIb) and 57 cases (25.6%) with poor response (CAP grade 3, 18 with Evans Grade I and 39 with Evans Grade IIa response). Patients with pCR or minimal residual tumor (response group 1) had better survivals than those with moderate and poor response (response group 2). Response group 1 patients had lower post-therapy tumor and AJCC stages, lower rates of lymph node metastasis, positive resection margin, and recurrence/metastasis. Grading the extent of residual tumor is an independent prognostic factor for OS in multivariate analysis. Conclusions pCR or minimal residual tumor in post-treatment PD specimens correlate with better survival in patients with PDAC who received neoadjuvant therapy and PD. Histologic grading of the extent of residual tumor in PD specimen is an important prognostic factor in patients with PDAC who received neoadjuvant therapies.

Background & Aims Obesity is a risk factor for pancreatic ductal adenocarcinoma (PDAC), but it is not clear how obesity contributes to pancreatic carcinogenesis. The oncogenic form of KRAS is expressed during early stages of PDAC development, and is detected in almost all of these tumors. However, there is evidence that mutant KRAS requires an additional stimulus to activate its full oncogenic activity, and that this stimulus involves the inflammatory response. We investigated whether the inflammation induced by a high-fat diet, and accompanying up-regulation of cyclooxygenase-2 (COX2), increases Kras activity during pancreatic carcinogenesis in mice. Methods We studied mice with acinar cell-specific expression of KrasG12D (LSL-Kras/Ela-CreERT mice) alone or crossed with COX2 conditional knockout mice (COXKO/LSL-Kras/Ela-CreERT). We also studied LSL-Kras/PDX1 -Cre mice. All mice were fed isocaloric diets with different amounts of fat, and a COX2 inhibitor was administered to some LSL-Kras/Ela-CreERT mice. Pancreata were collected from mice and analyzed for Kras activity, levels of phosphorylated ERK, inflammation, fibrosis, pancreatic intraepithelial neoplasia (PanIN), and PDACs. Results Pancreatic tissues from LSL-Kras/Ela-CreERT mice fed high-fat diets (HFDs) had increased Kras activity, fibrotic stroma, and numbers of PanINs and PDACs than LSL-Kras/Ela-CreERT mice fed control diets; the mice fed the HFDs also had shorter survival times than mice fed control diets. Administration of a COX2 inhibitor to LSL-Kras/Ela-CreERT mice prevented these effects of HFDs. We also observed a significant reduction in survival times of mice fed HFDs. COXKO/LSL-Kras/Ela-CreERT mice fed HFDs had no evidence for increased numbers of PanIN lesions, inflammation, or fibrosis, as opposed to the increases observed in LSL-Kras/Ela-CreERT mice fed HFDs. Conclusions In mice, a HFD can activate oncogenic Kras via COX2, leading to pancreatic inflammation and fibrosis, and development of PanINs and PDAC. This mechanism could be involved in the association between risk for PDAC and HFDs.

Background. The therapeutic resistance of pancreatic ductal adenocarcinoma (PDAC) is partly ascribed to ineffective delivery of chemotherapy to cancer cells. We hypothesized that physical properties at vascular, extracellular, and cellular scales influence delivery of and response to gemcitabine-based therapy.Methods. We developed a method to measure mass transport properties during routine contrast-enhanced CT scans of individual human PDAC tumors. Additionally, we evaluated gemcitabine infusion during PDAC resection in 12 patients, measuring gemcitabine incorporation into tumor DNA and correlating its uptake with human equilibrative nucleoside transporter (hENT1) levels, stromal reaction, and CT-derived mass transport properties. We also studied associations between CT-derived transport properties and clinical outcomes in patients who received preoperative gemcitabine-based chemoradiotherapy for resectable PDAC.Results. Transport modeling of 176 CT scans illustrated striking differences in transport properties between normal pancreas and tumor, with a wide array of enhancement profiles. Reflecting the interpatient differences in contrast enhancement, resected tumors exhibited dramatic differences in gemcitabine DNA incorporation, despite similar intravascular pharmacokinetics. Gemcitabine incorporation into tumor DNA was inversely related to CT-derived transport parameters and PDAC stromal score, after accounting for hENT1 levels. Moreover, stromal score directly correlated with CT-derived parameters. Among 110 patients who received preoperative gemcitabine-based chemoradiotherapy, CT-derived parameters correlated with pathological response and survival.Conclusion. Gemcitabine incorporation into tumor DNA is highly variable and correlates with multiscale transport properties that can be derived from routine CT scans. Furthermore, pretherapy CT-derived properties correlate with clinically relevant endpoints.Trial registration. Clinicaltrials.gov NCT01276613.

Perineural invasion (PNI) is one of the established prognostic factors in pancreatic ductal adenocarcinoma (PDAC). However, the prognostic significance of PNI in patients with PDAC who received neoadjuvant therapy and pancreaticoduodenectomy (PD) is not clear. In this study, we performed detailed examination of neural invasion in PD specimens from 212 patients with PDAC who received neoadjuvant chemoradiation (treated group) and 60 untreated patients at our institution between January 1999 and December 2007. The frequency of PNI was higher in untreated group (80%, 48/60) than the treated group (58%, 123/212). For the 123 treated cases that were positive for PNI, extra-tumoral PNI, intra-tumoral PNI, intra-pancreatic PNI only, extra-pancreatic PNI, and intra-neural invasion were identified in 86 (69.9%), 37 (30.1%), 11 (8.9%), 112 (91.1%), and 35 (28.5%) respectively. Presence of PNI correlated with tumor size, margin status, lymph node metastasis, pathologic tumor and AJCC stages in the treated group. Tumor involvement of nerves >0.8 mm correlated with higher frequency of positive margin compared to those with PNI involving nerves ≤0.8 mm, but not with other clinicopathologic parameters and survival. In treated group, the presence of PNI or intra-neural invasion correlated significantly with shorter disease-free survival (DFS) and overall survival (OS) compared to those with no PNI or PNI only respectively. PNI was an independent prognostic factor for both DFS and OS in multivariate analysis. Our results showed that PNI plays an important role in the progression of PDAC and in predicting the prognosis in this group of patients.